PROJECT SUMMARY/ABSTRACT Novel strategies to prevent and treat stroke that are both safe and effective are desperately needed in order to alleviate the burden of post-stroke disability. Statins are widely used for secondary stroke prevention; however, concerns with regard to potential long-term side effects to date prevented prophylactic use of statins in patients at high-risk for stroke. In acute ischemic stroke (AIS), cerebral tissue damage and clinical outcomes have been linked to microvascular dysfunction, manifesting as white matter hyperintensity (WMH) on brain MRI. WMH burden is associated with infarct growth, hemorrhagic transformation, and worse clinical AIS outcomes. In AIS, vascular protective effects of statins may alleviate the degree of microvascular dysfunction and improve cerebral tissue and clinical outcomes, but this requires further investigation. We hypothesize that pre-stroke statin use in subjects with advanced WMH improves cerebral perfusion and decreases blood-brain barrier (BBB) disruption during AIS. In addition, patients with advanced WMH may derive additional benefits in cerebral perfusion and functional outcomes after AIS with early post-stroke statin initiation. We propose to investigate the effect of statin use on outcomes after stroke, utilizing WMH severity as a clinical model of microvascular dysfunction. Using a collaborative approach, we propose to: (1) determine whether pre-stroke statin use modifies the neuroimaging and plasma biomarkers of microvascular dysfunction and ischemic tissue fate in subjects with advanced WMH and AIS; and (2) assess whether statin exposure improves survival and functional outcomes in AIS subjects with advanced WMH. Neuroimaging and plasma biomarkers obtained before and after initiation of statin in subjects with AIS and advanced WMH will provide proof-of-concept data on the impact of statin therapy on microvascular dysfunction, and its role in cerebral tissue susceptibility to acute ischemia. This study will bridge a critical gap in knowledge about the effect and timing of statin therapy in the evolution of stroke. It addresses pre-emptive therapeutic AIS strategies to improve post-stroke outcomes. If successful, this study will provide data to support prophylactic use of statins in patients who are high-risk for stroke based on their WMH burden, and ultimately, it may lead to change in our standard of practice for primary stroke prevention, clarify the optimal window for initiation of statin therapy, and decrease the burden of post-stroke disability.